Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor alpha.

Endothelial cells initiate the inflammatory response by recruiting and activating leukocytes. IL-6 is not an agonist for this, but we found soluble IL-6 receptor alpha-subunit (IL-6Ralpha), with their constitutive IL-6 synthesis, stimulated endothelial cells to synthesize E-selectin, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, IL-6, and IL-8, and to bind neutrophils. Neutrophils express significant amounts of IL-6Ralpha and upon stimulation shed it: this material activates endothelial cells through a newly constituted IL-6 receptor. Retrograde signaling from PMN activated in the extravascular compartment to surrounding endothelial cells will recruit more and a wider variety of leukocytes. The limiting signal is a soluble receptor, not a cytokine.     

A survey of ward nurses attitudes to the Intensive Care Nurse Consultant service in a teaching hospital

The aim of an Intensive Care Nurse Consultant (ICNC) service is to optimise care of complex ward patients and reduce adverse events. Despite their widespread implementation, specific assessment of ward nurses' attitudes towards such is lacking. Accordingly, we surveyed ward nurses' attitudes towards our ICNC service in five domains: (a) accessibility and approachability; (b) perceived ICNC skill and knowledge; (c) perceived influence on patient management; (d) usefulness as a resource of clinical information; (e) impact upon adverse outcomes. To achieve this, an anonymous Liker-type questionnaire was distributed to 208 ward nurses in our hospital. We also included space for free text. Completed questionnaires were entered manually into a SURVEYMONKEY? pro-forma to permit automatic report generation and results summary. The major findings were that ICNC staff were perceived as being approachable and good communicators, were skilled at early detection of deteriorating patients, and that they reduce serious adverse events. In addition, nurses believe the ICNC service provides continuity of care post discharge from the intensive care unit (ICU), as well as assisting staff to prioritise clinical issues following medical emergency team (MET) review or ICU discharge. The ward nurses did not believe that the ICNC service reduced their skills in managing ward patients. In contrast, respondents stated that the ICNC service needed to improve the processes of referral to allied health and education of ward staff regarding deteriorating patients. Finally, ward nurses suggest they would call the MET service rather than the ICNC service for patients who had already deteriorated. This survey suggests that the ICNC service is valued, and is perceived to prevent the development of adverse events, rather than playing a major role in the management of the deteriorating patient. There is a need to improve referrals to allied health and further educate ward nurses.     

An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells

PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2)-restricted leukemia-associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML). We report a novel T-cell receptor (TCR)-like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [K(D)] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin(-)CD34(+)CD38(-) leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA-A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML.     

Cough symptoms in children aged 5–14 years in Sydney,Australia: non‐specific cough or unrecognized pertussis?

OBJECTIVE: The aim of this study was to estimate the community prevalence of coughing symptoms, consistent with surveillance definitions for pertussis, and doctor-diagnosed pertussis in children aged 5-14 years. METHODOLOGY: A telephone survey of a cross-sectional community sample of parents regarding their child's cough symptoms in the previous 12 months was undertaken in a representative Australian urban region. RESULTS: In 2020 interviews, parents reported that 22% of children had a cough lasting 2 weeks or longer in the preceding 12 months, and 14% (283) had additional symptoms meeting the Centers for Disease Control (CDC) case definition for pertussis. A cough meeting the case definition was significantly more commonly reported by parents of children aged 5-9 years (17%; P < 0.001) but reported exposure to diagnosed pertussis in such cases was significantly more common in children aged 10-14 years (4.3%; odds ratio 12.8; P < 0.01). Parents of 90% of children meeting the CDC case definition sought medical advice. A diagnosis of pertussis was reported in only 1.2% of cases, which extrapolates to an annual incidence of doctor-diagnosed pertussis of 347/100,000 (95% confidence interval, 140-714 per 100,000). This contrasts with 29/100,000 notified cases in the same age group, time period and geographic area. CONCLUSION: Cough episodes meeting a clinical case definition for pertussis commonly used in surveillance are reported by a high proportion of carers of school-aged children in Australia. The majority of children who met the CDC and Australian case definitions for pertussis and sought medical attention were not identified as potentially having pertussis, suggesting underdiagnosis of pertussis. Even if less than half of this is true pertussis, the potential impact in terms of transmission of pertussis in the community is likely to be high. The reported incidence of doctor-diagnosed disease estimated from this survey was at least five and up to 20 times the official notification rate. More work needs to be done in raising awareness among medical practitioners of pertussis as a differential diagnosis in older children and adolescents with cough.     

A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers

BACKGROUND: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy. METHODS: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan-Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis. RESULTS: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5-15.0] and 16.3% (95% CI,13.4-19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1-3.2; P = 0.032), maternal CD4 cell count < 500 x 10(6) cells/l (OR, 2.5; 95% CI,1.3-5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0-6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3-3.8; P = 0.006). CONCLUSION: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.     

Surgical intervention for drug-resistant ventricular tachycardia

Endocardial resection was required in 26 patients with sustained drug-resistant ventricular tachycardia. The early mortality rate (within 30 days after operation) was 12%. Two deaths were the result of low cardiac output, and the third death was related to recurrent ventricular septal defect after septal endocardial resection. The survivors of endocardial resection were followed up from 6 to 92 months (mean 43). There were no recurrences of ventricular arrhythmias, and patients did not require antiarrhythmic drug therapy. The late mortality rate after endocardial resection was 19%. There were two late cardiac-related deaths (unrelated to arrhythmias) and three late deaths from noncardiac causes. Complete endocardial resection successfully ablates drug-resistant ventricular tachycardia, but is associated with an increased perioperative mortality rate in those patients who have severely depressed left ventricular function without a well defined left ventricular aneurysm.     

Treatment of achalasia: the short-term response to botulinum toxin injection seems to be independent of any kind of pretreatment

Background  

It has been suggested that intrasphincteric injection of botulinum toxin (BTX) may represent an alternative therapy to balloon dilatation in achalasia. The aim of the present study was to test the effectiveness of botulinum toxin injections in achalasia patients, as assessed using lower oesophageal sphincter pressure (LOSP) and symptom scores, and to compare the response in patients with different types of pretreatment (no previous treatment, balloon dilatation, myotomy, BTX injection).     

Antiphospholipid antibodies. Risk assessments for solid organ, bone marrow, and tissue transplantation

The literature pertaining to transplantation of solid organs, bone marrow, and other tissues in aPL-positive patients has been reviewed. The effects that aPL have relative to BMT are altogether different than those ascribed to solid organs and tissues. By definition, the transplantation of allogeneic bone marrow serves to reconstitute the recipient with a completely new and genetically different repertoire of antibody-producing cells. Previously aPL-positive bone marrow recipients become aPL-negative subsequent to transplantation assuming that the marrow donor is aPL-negative. These observations are the basis for contemporary experimental approaches to curing certain autoimmune diseases with BMT. Similarly, it would follow that an aPL-negative patient provided cells from an aPL-positive donor could become aPL-positive and suffer increased risk for thrombosis. From the data provided in most of the non-bone marrow publications, the presence of aPL should be considered a grave risk factor for any potential solid organ or tissue transplant candidate. Peritoneal dialysis patients seem to be at maximal risk. Given the serious emotional and economic impact of irreversible thrombotic loss suffered by organ transplant recipients, these factors alone should justify the modest expense of pretransplant aPL screening. In the United States, the average cost of losing a kidney transplant to aPL-associated thrombosis was estimated from 1996 data to be $82,000. The cost of losing a heart or liver is measured not only in dollars but often in the patient's life. The encouraging news, however, is that once aPL are identified before transplantation, prophylactic anticoagulation seems to be capable of forestalling untoward aPL-associated allograft events. Clearly, much remains to be discovered in exploring the pathobiologic characteristics of aPL in the laboratory as well as in neutralizing their procoagulant effects at the bedside.     

DSM-5 mixed specifier for manic episodes: Evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data

Background

To describe the frequency of mixed specifier as proposed in DSM-5 in bipolar I patients with manic episodes, and to evaluate the effect of mixed specifier on symptom severity and treatment outcome.

Methods

This post-hoc analysis used proxies for DSM-5 mixed features specifier by using MADRS or PANSS items.

Results

Of the 960 patients analysed, 34%, 18% and 4.3% of patients, respectively, had ≥3 depressive features with mild (score ≥1 for MADRS items and ≥2 for PANSS item), moderate (score ≥2 MADRS, ≥3 PANSS) and severe (score ≥3 MADRS, ≥4 PANSS) symptoms. In patients with ≥3 depressive features and independent of treatment: MADRS remission (score ≤12) rate decreased with increasing severity (61–43%) and YMRS remission (score ≤12) was similar for mild and moderate patients (36–37%), but higher for severe (54%). In asenapine-treated patients, the MADRS remission rate was stable regardless of baseline depressive symptom severity (range 64–67%), whereas remission decreased with increasing severity with olanzapine (63–38%) and placebo (49–25%). Reduction in YMRS was significantly greater for asenapine compared with placebo at day 2 across the 3 severity cut-offs and continued to decrease throughout the treatment period. The difference between olanzapine and placebo was statistically significant in mild and moderate patients.

Limitations

Results are from post-hoc analyses.

Conclusions

These analyses support the validity of proposed DSM-5 criteria. They confirm that depressive features are frequent in bipolar patients with manic episodes. With increasing baseline severity of depressive features, treatment outcome was poorer with olanzapine and placebo, but remained stable with asenapine.